2026-07-11 | Efficacy and safety of recombinant activated factor VII for secondary prophylaxis in patients with Glanzmann thrombasthenia.
Glanzmann thrombasthenia (GT) is a rare inherited platelet disorder associated with recurrent and sometimes life-threatening bleeding. Recombinant activated factor VII (rFVIIa) is approved for treatment of bleeding episodes or surgical prophylaxis in patients with GT who are refractory or alloimmunized to platelet transfusions. However, evidence for its use as secondary prophylaxis remains scarce. This study described the efficacy and safety of rFVIIa secondary prophylaxis in patients with GT and recurrent and uncontrolled bleeding despite standard therapy. A multicenter, retrospective study of patients with GT included in the Spanish Registry of Patients with Inherited Platelet Disorders (RETPLAC) was performed. We evaluated bleeding severity using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool (BAT) and calculated the annualized bleeding rate (ABR) before and during rFVIIa prophylaxis. Of the 37 patients with GT included in RETPLAC, 4 patients received regular rFVIIa prophylaxis due to recurrent severe bleeding. Median baseline ISTH-BAT score was 13.5 (IQR, 9.5-18), and median preprophylaxis ABR was 3 (IQR, 3-5.25). All patients received rFVIIa of 90 μg/kg, 3 twice weekly and 1 monthly. The median prophylaxis duration was 7.5 months (IQR, 6.75-12). Prophylaxis led to a 57.1% overall reduction in ABR, with resolution of severe bleeding in 2 patients and reduction in frequency in the remaining 2. Three patients achieved transfusion independence. All patients showed improvement in hemoglobin and iron profile. No thrombotic or adverse events occurred. Secondary prophylaxis with rFVIIa may be an effective option in patients with GT and recurrent severe bleeding unresponsive to standard therapy. Prospective studies are necessary to optimize dosing schedules and define its role in secondary prophylaxis.
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2026-07-09 | [Current diagnosis and treatment of congenital platelet function disorders: focus on Glanzmann thrombasthenia and Bernard-Soulier syndrome].
Platelet function is regulated by numerous molecules, and congenital abnormalities of these molecules result in a variety of congenital platelet function disorders. Among these, Glanzmann thrombasthenia (GT), caused by a congenital deficiency or molecular abnormality in GPIIb-IIIa (αIIbβ3), and Bernard-Soulier syndrome (BSS), caused by a congenital deficiency or molecular abnormality in the GPIb-IX-V complex, are representative disorders that manifest as severe bleeding tendency from infancy. GT and BSS are diagnosed mainly by flow cytometry of membrane glycoproteins in addition to conventional light transmission aggregometry. Platelet transfusions are indicated for bleeding refractory to standard hemostatic measures, and recombinant factor VIIa (rFVIIa) has been shown to be effective in GT. rFVIIa has conventionally been used in GT patients refractory to platelet transfusion due to alloantibody production, but is now available in Japan regardless of alloantibody status or platelet transfusion refractoriness. rFVIIa should be considered especially in patients at risk of alloantibody production due to platelet transfusion.
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2026-05-29 | Reduced platelet formation associated with serine metabolic dysregulation in integrin αIIbβ3-deficient megakaryocytes.
Glanzmann Thrombasthenia (GT) is characterized by absent platelet aggregation in response to all agonists except ristocetin and is caused by recessive inactivating variants in ITGA2B or ITGB3. While GT patients typically are described as having normal platelet counts, autosomal dominant activating variants in ITGA2B or ITGB3 cause macrothrombocytopenia. Interestingly, in our cohort of 16 GT patients, eight consistently exhibited platelet counts at the lower end of the normal range. We studied the role of integrin αIIbβ3 in platelet formation using megakaryocytes (MKs) derived from genetically modified immortalized megakaryocyte cell lines (imMKCLs), focusing on two modifications of ITGB3: ITGB3-/- (inactivating) and ITGB3WT/D673_E713del (activating). In static differentiation cultures, ITGB3-/- and ITGB3WT/D673_E713del imMKCLs exhibited normal MK differentiation but reduced proplatelet formation. Platelet production was also impaired in a 3D silk-based bone marrow system and in shaking cultures, confirming a quantitative role for ITGB3 in platelet production, independent of the type of variant. While TRAP-activated in vitro-generated platelets lacking αIIbβ3 failed to bind the activation-dependent PAC-1 antibody, ITGB3WT/D673_E713del platelets bound PAC-1 prior to activation mimicking the patient's phenotype. Transcriptome profiling and metabolomic analyses of integrin αIIbβ3 deficient MKs revealed impaired serine metabolism and downregulation of SLC3A2 (CD98hc), an amino acid transporter chaperon known to interact with the β3 subunit. Flow cytometry confirmed decreased CD98hc in mutant MKs, while re-expression of wild-type ITGB3 in ITGB3-/- MKs restored αIIbβ3 and CD98hc expression, normalized proplatelet formation, and enhanced serine uptake. These results uncover a previously unrecognized role of integrin αIIbβ3 in coupling serine metabolism to platelet biogenesis.
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